Imidazolamino compounds

ABSTRACT

The invention relates to novel imidazolamino compounds. Also disclosed are methods of treating cancer by using one of these compounds and pharmaceutical compositions containing one of these compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/406,363, filed Aug. 26, 2002, the contents of which areincorporated herein by reference.

BACKGROUND

Cancer is one of the most common causes of death in developed countries.Despite continuing advances, most existing cancer treatments haveundesirable side effects and limited efficacy. Identifying new effectiveanti-cancer drugs has always been the focus of cancer research.

Imidazolamino compounds have been demonstrated in animal models ofnon-insulin-dependent diabetes mellitus to both improve insulinsensitivity and promote weight loss selectively from adipose tissue.Indeed, some of them are anti-diabetic drugs. See, e.g., J. Med. Chem.,2001, 44, 1231-1248. However, no imidazolamino compounds have beenreported to possess anti-cancer activities.

SUMMARY

One aspect of this invention relates to imidazolamino compounds offormula (I)

In formula (I), X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each ofR_(a) and R_(b), independently, is hydrogen, halo, alkyl, haloalkyl,arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl,arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl isoptionally substituted with alkoxy, halo, nitro, cyano, haloalkyl; andeach of R_(c) and R_(d), independently, is hydrogen; halo; alkyl;heteroaryl; phenyl optionally substituted with hydroxy, halo, alkyl,haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano,halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo,or amino; naphthylsulfonyl substituted with cyano, halo, oxo, or amino;naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyloptionally substituted with halo, phenyl or imidazolyl, or phenyl orimidazolyl optionally substituted with alkyl, halo, or hydroxy. R₁ iscycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, optionallyfused to aryl, heteroaryl, cycloalkyl, or heterocyclyl; hydrogen; halo;alkyl; haloalkyl; alkenyl; or alkynyl. R₂ is hydrogen, alkyl,cycloalkyl, cycloalkenyl, phenyl, thienyl, thiazolyl, anthryl, orquinolyl, optionally substituted with hydroxy, halo, cyano, alkyl,haloalkyl, nitro, or alkoxy. R₃ is hydrogen, alkyl, or phenyl optionallysubstituted with hydroxy, halo, alkyl, haloalkyl, cyano, nitro, oralkoxy. R₄ is biphenyl, thienyl, pyridinyl, thiazolyl, anthryl,naphthyl, or quinolyl, optionally substituted with hydroxy, halo, alkyl,haloalkyl, nitro, or alkoxy, when R₂ is thienyl, thiazolyl, anthryl, orquinolyl, optionally substituted with hydroxy, halo, alkyl, haloalkyl,cyano, nitro, or alkoxy; is diphenyl, thienyl, pyridinyl, thiazolyl,anthryl, naphthyl, or quinolyl, optionally substituted with hydroxy,halo, alkyl, haloalkyl, cyano, nitro, or alkoxy, when R₂ is phenyloptionally substituted with hydroxy, alkyl, haloalkyl, or alkoxy; ispyridinyl, thiazolyl, anthryl, naphthyl, or quinolyl, optionallysubstituted with hydroxy, halo, alkyl, haloalkyl, nitro, or alkoxy, whenR₂ is phenyl optionally substituted with chloro, bromo, iodo, or nitro;is phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl,nitro, or alkoxy when R₂ is phenyl substituted with fluoro, alkyl, orhaloalkyl; or is alkyl, cycloalkyl, cycloalkenyl, or heterocyclyloptionally substituted with hydroxy, halo, alkyl, cyano, nitro,haloalkyl or alkoxy, when R₂ is hydrogen, alkyl, cycloalkyl,cycloalkenyl, thienyl, thiazolyl, anthryl, or quinolyl, optionallysubstituted with hydroxy, halo, alkyl, haloalkyl, cyano, or alkoxy.

The term “halo” refers to any radical of fluorine, chlorine, bromine oriodine. The term “alkyl,” independently or as a prefix (e.g., alkoxy) orsurfix (e.g., haloalkyl), refers to a hydrocarbon chain that may be astraight chain or branched chain of C₁₋₁₂. The term “alkylene” refers toa divalent alkyl (i.e., —R—) of C₁₋₁₂. The term “aryl” refers to a6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.Examples of aryl groups include phenyl, naphthyl and the like. The term“heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12membered bicyclic, or 11-14 membered tricyclic ring system comprising1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by asubstituent. Examples of heteroaryl groups include pyridyl, furyl orfuranyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl,quinolinyl, indolyl, thiazolyl, and the like. The term “heteroarylalkyl”or the term “heteroaralkyl” refers to an alkyl substituted with aheteroaryl. The term “heteroarylalkoxy” refers to an alkoxy substitutedwith heteroaryl.

Subsets of the compounds include those in which R₂ is thienyl,thiazolyl, anthryl, or quinonlyl, optionally substituted with hydroxy,halo, alkyl, haloalkyl, nitro, or alkoxy; or phenyl substituted withhydroxy, fluoro, chloro, bromo, alkyl, or alkoxy; those in which R₄ isphenyl, pyridinyl, thiazolyl, anthryl, or quinonlyl, optionallysubstituted with hydroxy (e.g., hydroxyanthryl), halo (e.g.,chloropyridinyl), alkyl (e.g., alkylphenyl), haloalkyl, nitro (e.g.,nitrothiazolyl), or alkoxy; and those in which X is NH₂; those in whichR₁ is hydrogen or heteroaryl; and R₃ is hydrogen or phenyl.

Specific examples of these compounds include

Another aspect of this invention relates to imidazolamino compounds offormula (II):

In formula (II), X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each ofR_(a) and R_(b), independently, is hydrogen, halo, alkyl, or haloalkyl;arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl,arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl isoptionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, andeach of R_(c) and R_(d), independently, is hydrogen; halo; alkyl;heteroaryl; phenyl optionally substituted with hydroxy, halo, alkyl,haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano,halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo,or amino; naphthylsulfonyl substituted with cyano, halo, oxo, or amino;naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyloptionally substituted with halo, phenyl or imidazolyl, or phenyl orimidazolyl optionally substituted with alkyl, halo, or hydroxy. Each ofR₁ and R₂, independently, is hydrogen, alkyl, or haloalkyl. R₃ is alkyl,phenyl, thienyl, pyridinyl, thiazolyl, cycloalkyl, cycloalkenyl,benzofuranyl, indolyl, pyrazinyl, pyrimidinyl, pyrrolyl,N-methylpyrrolyl, isothiazolyl, oxadiazolyl, furyl, isoazolyl, oxazolyl,or heterocyclyl optionally substituted with halo, alkyl, haloalkyl,hydroxy, or amino. R₄ is hydrogen, alkyl, hydroxy, or amino. R₅ ishydrogen, alkyl, or aryl optionally substituted with hydroxy, halo,alkyl, haloalkyl, or amino. R₆ is hydrogen, fluorophenyl, naphthyl,thienyl, pyridinyl, furyl, thiazolyl cycloalkyl, cycloalkenyl,benzofuranyl, indolyl, pyrazinyl, pyrimidinyl, pyrrolyl,N-methylpyrrolyl, isothiazolyl, oxadiazolyl, isoazolyl, oxazolyl, orheterocyclyl when R₃ is alkyl optionally substituted with halo, hydroxy,or amino, or is phenyl optionally substituted with halo, hydroxy, amino,or alkyl; and R₅ is hydrogen, alkyl, or aryl optionally substituted withhydroxy, alkyl, or amino, or is phenyl optionally substituted withhydroxy, halo, alkyl, haloalkyl, or amino when R₃ is thienyl, pyridinyl,or thiazolyl, optionally substituted with halo, alkyl, haloalkyl, orhydroxy, and R₅ is hydrogen, alkyl, or phenyl optionally substitutedwith hydroxy, halo, alkyl, haloalkyl, or amino

Subset of the compounds of formula (II) include those in which R₆ ishydrogen, fluorophenyl, naphthyl, thienyl, pyridinyl, furyl, orthizaolyl, when R₃ is alkyl optionally substituted with halo, hydroxy,or amino, or is phenyl optionally substituted with halo, hydroxy, amino,or alkyl; and when R₅ is hydrogen, alkyl, or aryl optionally substitutedwith hydroxy, alkyl, or amino; those in which X is NH₂; those in whichR₄ is H; those in which R₃ is phenyl or alkyl, optionally substitutedwith halo; and R₅ is hydrogen or phenyl.

Specific examples of the compound of formula (II) include

Still another aspect of this invention relates to imidazolaminocompounds of formula (III):

In formula (III), X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each ofR_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl,heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, orarylsulfonyl, in which aryl or heteroaryl is optionally substituted withalkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substitutedwith halo; and each of R_(c) and R_(d), independently, is hydrogen,halo, or phenyl optionally substituted with hydroxy, halo, alkyl,haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano,halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo,or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, oramino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; oralkyl optionally substituted with halo, phenyl optionally substitutedwith alkyl, halo, or hydroxy, or imidazolyl optionally substituted withalkyl, halo, or hydroxy; R₁ is alkyl, phenyl, haloalkylphenyl,phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl,phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl,phenylaminocarbonyl, or phenylsulfonyl, optionally substituted withalkoxy, halo, cyano, nitro, or haloalkyl; or hydrogen; R₂ is hydrogen,alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl,optionally substituted with halo; and R₃ is hydrogen, furyl, thienyl,pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with haloor alkyl. Alternatively, X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in whicheach of R_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl,heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, orarylsulfonyl, in which aryl or heteroaryl is optionally substituted withalkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substitutedwith halo; and each of R_(c) and R_(d), independently, is hydrogen,halo, or phenyl optionally substituted with hydroxy, halo, alkyl,haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano,halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo,or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, oramino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; oralkyl optionally substituted with halo, phenyl optionally substitutedwith alkyl, halo, or hydroxy, or imidazolyl optionally substituted withalkyl, halo, or hydroxy; R₁ is alkyl, haloalkylphenyl, phenylalkyl,diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl,furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl,or phenylsulfonyl, optionally substituted with alkoxy, halo, nitro, orhaloalkyl; or hydrogen; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl,pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo;and R₃ is phenyl optionally substituted with halo, alkoxy or alkyl. Asyet another alternative, X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in whicheach of R_(a) and R_(b), independently, is hydrogen or alkyl, arylalkyl,heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, orarylsulfonyl, in which aryl or heteroaryl is optionally substituted withalkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substitutedwith halo; and each of R_(c) and R_(d), independently, is hydrogen,halo, or phenyl optionally substituted with hydroxy, halo, alkyl,haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano,halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo,or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, oramino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; oralkyl optionally substituted with halo, phenyl optionally substitutedwith alkyl, halo, or hydroxy, or imidazolyl optionally substituted withalkyl, halo, or hydroxy; R₁ is hydrogen, alkyl, phenyl, haloalkylphenyl,phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl,phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl,phenylaminocarbonyl, or phenylsulfonyl, in which phenyl, furyl, thienyl,pyridinyl, oxadiazolyl, or isoxazolyl is optionally substituted withalkoxy, halo, nitro, or haloalkyl; R₂ is hydrogen, alkyl, phenyl, furyl,thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substitutedwith halo; and R₃ is hydrogen, furyl, thienyl, pyridinyl, oxadiazolyl,or isoxazolyl, optionally substituted with halo or alkyl.

Subsets of the compounds of formula (III) includes those in which X isNH₂; those in which R₂ is hydrogen; and those in which R₃ is phenyl,furyl, or thienyl. Specific examples of these compounds include

The imidazolamino compounds described above include their salts, ifapplicable. Such a salt, for example, can be formed between a positivelycharged substituent, e.g., amino, and an anion. Suitable anions include,but are not limited to, chloride, bromide, iodide, sulfate, nitrate,phosphate, or acetate. Likewise, a negatively charged substituent (e.g.,carboxylate) can form a salt with a cation. Suitable cations include,but are not limited to, sodium ion, potassium ion, magnesium ion,calcium ion, and an ammonium cation such as tetramethylammonium ion.

The compounds of this invention can be used as anti-cancer drugs. Thus,also within the scope of this invention are pharmaceutical compositionseach containing a pharmaceutically acceptable carrier and one of theabove-described compounds; and methods for treating cancer, whichinclude administering to a subject in need thereof an effective amountof an above-described compound.

The details of several embodiments of the invention are set forth in theaccompanying description below. Other features, objects, and advantagesof the invention will be apparent from the description and from theclaims.

DETAILED DESCRIPTION

Imidazolamino compounds of this invention generally can be synthesizedfrom an aminoguanidine compound by first coupling it with a carbonylcontaining compound (e.g., an aldehyde) to form an iminoguinidineadduct. The iminoguinidine adduct can then react with a haloacetocompound (e.g., bromoacetofuryl) via a ring-form mechanism to form animidazolyl ring. Shown below is Scheme 1, which depicts a method forpreparing some imidazol amino compounds of this invention.

Starting materials containing different substituents on Ar₁ and Ar₂ canbe used to prepare imidazolamino compounds containing varioussubstituents on Ar₁ or Ar₂ by following the same reaction scheme.

The 2-amino group in the imidazolamino compounds can be modified asshown below in Schemes 2, 3, and 4:

The imidazolamino compounds containing a thiazolyl ring at 1-N can besynthesized, as shown below in Scheme 5, by using amidinothiourea in amethod similar to that depicted in Scheme 1:

Like other imidazolamino compounds, the 2-amino group of the above-shownthiazolylimidazolamino compound can be modified as shown in Schemes 2-4.

As mentioned above, the compounds of this invention can be used toinhibit the growth of (including killing) cancer cells. Thus, anotheraspect of this invention relates to a pharmaceutical composition whichcontains an effective amount of at least one of the compounds describedabove (or its salt) and a pharmaceutically acceptable carrier fortreating cancer. “An effective amount” refers to the amount of thecompound which is required to confer a therapeutic effect on the treatedsubject. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described inFreireich et al., Cancer Chemother. Rep., 1966, 50, 219. Body surfacearea may be approximately determined from height and weight of thepatient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley,N.Y., 1970, 537. Effective doses will also vary, as recognized by thoseskilled in the art, depending on route of administration, excipientusage, and the possibility of co-usage with other therapeutic treatmentsincluding use of other anti-platelet aggregation agents. Examples of thecarriers include colloidal silicon dioxide, magnesium stearate,cellulose, sodium lauryl sulfate, and D&C Yellow # 10.

The pharmaceutical composition may be administered via a parenteralroute, e.g., topically, subcutaneously, intraperitoneally,intramuscularly, and intravenously. Examples of parenteral dosage formsinclude aqueous solutions of the active compound, in an isotonic saline,5% glucose, or any other well-known pharmaceutically acceptable carrier.Solubilizing agents, such as cyclodextrins, or other solubilizing agentswell known to those familiar with the art, can also be included in thepharmaceutical composition.

An imidazolamino compound of this invention can be formulated intodosage forms for other routes of administration (e.g., orally,mucosally, or percutaneously) utilizing well known methods. Thepharmaceutical composition can be formulated, for example, in dosageforms for oral administration in a capsule, a gel seal, or a tablet.Capsules may comprise any well known pharmaceutically acceptablematerial such as gelatin or cellulose derivatives. Tablets may beformulated in accordance with the conventional procedure by compressingmixtures of the active compounds, a solid carrier, and a lubricant.Examples of solid carriers include starch and sugar bentonite. Thecompound can also be administered in a form of a hard shell tablet orcapsule containing, for example, lactose or mannitol as a binder, aconventional filler, and a tableting agent.

As mentioned above, the imidazolamino compounds of this invention haveanti-cancer activities. Their activities can be evaluated by in vitroand in vivo assays well known in the art. For instance, a panel of humancancer cell lines can be first seeded in a medium, incubated, andbrought in contact with a compound. The anti-cancer (cytotoxic)acitivities can then be determined by evaluating the viability of thecells. An in vivo assay can be conducted by using mice inoculated withcancer cells, followed by administration of the compounds of thisinvention. The efficacy of the compound can then be confirmed bymonitoring the survival rate of these mice.

Without further elaboration, it is believed that one skilled in the artcan, based on the description herein, utilize the present invention toits fullest extent. All publications recited herein are herebyincorporated by reference in their entirety. The following specificexamples, which describe synthesis and biological testing of variouscompounds of the present invention, are therefore, to be construed asmerely illustrative, and not limitative of the remainder of thedisclosure in any way whatsoever.

EXAMPLE 1 Synthesis ofN1-[(E)-1-(4-fluorophenyl)methylidene]-4-phenyl-1H-1,2-imidazolediamine(Compound 1)

A mixture of 4-fluorobenzaldehyde (2.0 g, 15.8 mmol), 20% hydrochloricacid (4 mL) was added to an aminoguanidine bicarbonate (2.2 g, 15.8mmol) aqueous solution. After completion of the liberation of carbondioxide, the mixture was heated for 4 h. A solution of 40% aqueouspotassium hydroxide (7 mL) was added and the mixture was heated atreflux for additional 10 min. The resulting solution was filtered,washed with water until the wash water was at pH 7, dried andrecrystallized from ethanol to give2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide (2.6 g,91%) as a yellow solid.

2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide (0.74g, 4.06 mmol) was added to a solution of 2-bromoacetophenone (0.40 g,2.03 mmol) in ethanol (10 mL), and the reaction was heated to 70° C. for4 h. A solution of sodium hydroxide aqueous solution was added dropwise.The yellow precipitate was formed and cooled the reaction mixture atroom temperature for additional 10 h, then filtered, washed with hotwater and recrystallized from ethanol to give 1 (0.44 g, 77%) as ayellow solid.

¹H NMR (DMSO-d₆): δ 8.56 (s, 1H), 8.01-7.96 (m, 3H), 7.69 (d, J=7.2 Hz,2H), 7.37-7.30 (m, 4H), 7.18 (t, J=7.2 Hz, 1H), 6.20 (s, 2H). ESMS m/z:281.5 (MH⁺).

EXAMPLE 2 Synthesis ofN1-[(E)-1-(4-chlorophenyl)methylidene]-4-(5-chloro-2-thienyl)-1H-1,2-imidazolediamine(Compound 2)

A mixture of 4-chlorobenzaldehyde (2.0 g, 10.2 mmol), 20% hydrochloricacid (4 mL) was added to an aminoguanidine bicarbonate (1.39 g, 10.2mmol) aqueous solution, and heated to reflux for 4 h. A solution of 40%aqueous potassium hydroxide (7 mL) was added dropwise, the mixture washeated at reflux for 10 min and the precipitate formed. The precipitatewas filtered, washed with water, and recrystallized from ethanol to give2-[(E)-1-(4-chlorophenyl)methylidene]-1-hydrazinecarboximidamide (1.77g, 88%) as a yellow solid.

A solution of 2-bromo-1-(5-chloro-2-thienyl)-1-ethanone (1.07 g, 4.49mmol), 2-[(E)-1-(4-chlorophenyl)methylidene]-1-hydrazinecarboximidamide(1.77 g, 8.98 mmol) was heated in ethanol (10 mL) for 2 h, then themixture was left at room temperature for additional 10 h. Theprecipitate filtered, washed with hot water, and recrystallized fromethanol to giveN1-[(E)-1-(4-chlorophenyl)methylidene]-4-(5-chloro-2-thienyl)-1H-1,2-imidazolediamine2 (1.09 g, 72%) as a brown solid.

¹H NMR (DMSO-d₆): δ 8.51 (s, 1H), 7.94 (d, J=7.8 Hz, 2H), 7.86 (s, 1H),7.57 (d, J=7.8 Hz, 2H), 7.05 (s, 2H), 6.39 (s, 2H). ESMS m/z: 337.4(MH⁺).

EXAMPLE 3 Synthesis ofN1-[(E)-1-(4-methoxyphenyl)methylidene]-4,5-diphenyl-1H-1,2-imidazolediamine(Compound 3)

A mixture of 4-anisaldehyde (2.0 g, 14.4 mmol), 20% hydrochloric acid (4mL) was added to an aminoguanidine bicarbonate (1.96 g, 14.4 mmol)aqueous solution, and heated to reflux for 4 h. 40% aqueous potassiumhydroxide (7 mL) was added and the mixture was heated at reflux foradditional 10 min. The mixture was cooled in room temperature for 10 hand a yellow precipitate formed. The yellow precipitate was filtered,washed with hot water and recrystallized from ethanol to give2-[(E)-1-(4-methoxyphenyl)methylidene]-1-hydrazinecarboximidamide (2.4g, 87%) as a yellow solid.

A solution of desyl bromide (1.72 g, 6.26 mmol), and2-[(E)-1-(4-methoxyphenyl)methylidene]-1-hydrazinecarboximidamide (2.4g, 12.5 mmol) was heated at reflux in ethanol (10 mL) for 2 h. Themixture was cooled at room temperature for additional 10 h, and a yellowprecipitate formed. The yellow precipitate was filtered, washed with hotwater and recrystallized from ethanol to giveN1-[(E)-1-(4-methoxyphenyl)methylidene]-4,5-diphenyl-1H-1,2-imidazolediamine3 (1.57 g, 68%) as a yellow solid.

¹H NMR (DMSO-d₆): δ 7.91 (s, 1H), 7.52 (d, J=9.0 Hz, 2H), 7.44-7.31 (m,6H), 7.19-7.06 (m, 4H), 6.98 (d, J=9.0 Hz, 2H), 5.92 (br, 2H), 3.79 (s,3H). ESMS m/z: 369.1 (MH⁺).

EXAMPLE 4 Synthesis ofN1-[(E)-1-(4-fluorophenyl)methylidene]-4-(1,3-thiazol-2-yl)-1H-1,2-imidazolediamine(Compound 4)

A mixture of 4-fluorobenzaldehyde (2.0 g, 15.8 mmol), 20% hydrochloricacid (4 mL) was added to an aminoguanidine bicarbonate (2.2 g, 15.8mmol) aqueous solution. After completion of the liberation of carbondioxide, the mixture was heated for 4 h. A solution of 40% aqueouspotassium hydroxide (7 mL) was added and the mixture was heated atreflux for additional 10 min. The resulting solution was cooled,filtered, washed with water until the wash water was at pH 7, dried andrecrystallized from ethanol to give2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide (2.6 g,91%) as a yellow solid.

A solution of 2-bromo-1-(1,3-thiazol-2-yl)-1-ethanone (1.5 g, 7.2 mmol),and 2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide(2.6 g, 14.4 mmol) was heated at reflux in ethanol (10 mL) for 2 h. Themixture was left at room temperature for additional 10 h, then theprecipitate was filtered, washed with hot water and recrystallized fromethanol to giveN1-[(E)-1-(4-fluorophenyl)methylidene]-4-(1,3-thiazol-2-yl)-1H-1,2-imidazolediamine 4 (1.45 g, 70%) as a yellow solid.

¹H NMR (DMSO-d₆): δ 8.74 (s, 1H), 8.12 (s, 1H), 8.03-7.97 (m, 2H),7.81-7.79 (m, 1H), 7.59-7.58 (m, 1H), 7.35 (t, J=8.0 Hz, 2H), 6.57 (br,2H). ESMS m/z: 288.0 (MH⁺).

EXAMPLE 5 Synthesis of1-(4-methyl-1,3-thiazol-2-yl)-4-phenyl-1H-2-imidazolamine (Compound 5)

A mixture of amidinothiourea (2.0 g, 16.9 mmol), chloroacetone (1.56 g,16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixturewas cooled to room temperature and removed half of the solvent. Theprecipitate was filtered, washed with dry acetone, and dried to giveN-(4-methyl-1,3-thiazol-2-yl)guanidine (2.19 g, 83%).

A solution of N-(4-methyl-1,3-thiazol-2-yl)guanidine (2.19 g, 14.0 mmol)and 2-bromoacetophenone (13.9 g, 7.0 mmol) in ethanol (5 mL) was heatedto 80° C. for 2 h. The mixture was left at room temperature foradditional 10 h, filtered, washed with hot water and recrystallized fromethanol to give 5 (1.38 g, 77%).

¹H NMR (DMSO-d₆): δ 7.78 (d, J=7.2 Hz, 2H), 7.63 (s, 1H), 7.35 (t, J=7.2Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 7.08 (s, 1H), 6.95 (br, 2H), 2.35 (s,3H). ESMS m/z: 257.0 (MH⁺), 279.0 (M+23)⁺.

EXAMPEL 6 Synthesis of1-(4-phenyl-1,3-thiazol-2-yl)-4-(2-thienyl)-1H-2-imidazolamine (Compound6)

A mixture of amidinothiourea (2.0 g, 16.9 mmol), 2-bromoacetophenone(3.4 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. Themixture was cooled to room temperature and removed half of the solvent.The precipitate was filtered, washed with acetone, and dried to giveN-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 87%).

A solution of N-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 14.7 mmol)and 2-bromo-1-(2-thienyl)-1-ethanone (1.5 g, 7.35 mmol) in ethanol (5mL) was heated to 80° C. for 2 h. The mixture was left at roomtemperature for additional 10 h, filtered, washed with hot water andrecrystallized from ethanol to give 6 (1.48 g, 62%).

¹H NMR (DMSO-d₆): δ 7.85 (d, J=6.9 Hz, 2H), 7.48-7.38 (m, 3H), 7.33 (d,J=3.3 Hz, 1H), 7.25-7.20 (m, 2H), 7.02-7.03 (m, 2H), 6.36 (br, 2H). ESMSm/z: 325.0 (MH⁺).

EXAMPLE 7 Synthesis of1-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-5-phenyl-1H-2-imidazolamine(Compound 7)

A mixture of amidinothiourea (2.0 g, 16.9 mmol), 2-bromoacetophenone(3.4 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. Themixture was cooled to room temperature and removed half of the solvent.The precipitate was filtered, washed with acetone, and dried to giveN-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 87%).

A solution of N-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 14.7 mmol)and 2-bromo-2-phenylacetaldehyde (1.46 g, 7.3 mmol) in ethanol (5 mL)was heated to 80° C. for 2 h. The mixture was left at room temperaturefor additional 10 h, filtered, washed with hot water and recrystallizedfrom ethanol to give 7 (1.65 g, 71%).

¹H NMR (CDCl₃): δ 8.08 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 7.35-7.19 (m, 5H), 6.82 (s, 1H), 6.50 (br, 2H). ESMS m/z: 353.0(MH⁺).

EXAMPLE 8 Synthesis of2,4-dibromo-6-[(1-[(E)-1-(4-fluorophenyl)methylidene]amino-4-phenyl-1H-2-imidazolyl)imino]methylphenol(Compound 8)

A mixture of 4-fluorobenzaldehyde (2.0 g, 15.8 mmol), 20% hydrochloricacid (4 mL) was added to an aminoguanidine bicarbonate (2.2 g, 15.8mmol) aqueous solution. After completion of the liberation of carbondioxide, the mixture was heated for 4 h. A solution of 40% aqueouspotassium hydroxide (7 mL) was added and the mixture was heated atreflux for additional 10 min. The resulting solution was filtered,washed with water until the wash water was at pH=7, dried andrecrystallized from ethanol to give2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide (2.6 g,91%) as a yellow solid.

A solution of sodium hydroxide (81 mg, 2.03 mmol) in ethanol (5 mL) wasadded dropwise over 20 min to a mixture of 2-bromoacetophenone (0.40 g,2.03 mmol), and2-[(E)-1-(4-fluorophenyl)methylidene]-1-hydrazinecarboximidamide (0.37g, 2.03 mmol) in ethanol (10 mL). The reaction was heated to 70° C. for2 h, and a yellow precipitate formed. The mixture was cooled at roomtemperature for additional 10 h, then filtered, washed with hot waterand recrystallized from ethanol to give 1 (0.44 g, 77%) as a yellowsolid.

To a solution ofN1-[(E)-1-(4-fluorophenyl)methylidene]-4-phenyl-1H-1,2-imidazole diamine1 (0.44 g, 1.56 mmol) and 3,5-dibromosalicyclaldehyde (0.44 g, 1.56mmol) was dissolved in EtOH (20 mL). The mixture was heated to refluxfor 2 h, and stirred at room temperature for further 2 h. The resultingsolution was filtered, washed with hot water, and recrystallized fromethanol to give 8 (0.7 g, 83%) as a yellow solid.

¹H NMR (DMSO-d₆): δ 9.41 (s, 1H), 9.01 (s, 1H), 8.67 (s, 1H), 8.12 (d,J=2.1 Hz, 1H), 7.98-7.92 (m, 3H), 7.88 (d, J=8.7 Hz, 2H), 7.49-7.43 (m,4H), 7.32 (t, J=7.5 Hz, 1H). ESMS m/z: 540.1 (MH⁺).

EXAMPLES 9-33

The following compounds were synthesized according to the methodsdescribed above:

Compound R¹ R² R³ R⁴ 9 3-methyl-2-thienyl H H phenyl 104-(trifluoromethyl)- H H phenyl phenyl 11 4-chloro-2-nitrophenyl H Hphenyl 12 3,4-dichlorophenyl H H phenyl 13 2,3-dichlorophenyl H H Phenyl14 2-chlorophenyl H H Phenyl 15 4-quinolyl H H Phenyl 1610-chloro-9-anthryl H H phenyl 17 4-chlorophenyl H H biphenyl 184-chlorophenyl H H 2-methoxyphenyl 19 4-fluorophenyl H H 3-thienyl 204-chlorophenyl H H 3-thienyl 21 4-chlorophenyl H H 2,4-dimethylphenyl 224-fluorophenyl H H 2-pyridyl 23 4-chlorophenyl H H 2-pyridyl 244-fluorophenyl H H 3-pyridyl 25 4-chlorophenyl H H 3-pyridyl 264-fluorophenyl H H 2-thienyl 27 4-chlorophenyl H H 2-thienyl 284-fluorophenyl H H 2,4-dichlorophenyl 29 4-chlorophenyl H H2,4-dichlorophenyl 30 4-chlorophenyl H H 2-naphthyl 31 4-fluorophenyl Hphenyl phenyl 32 4-chlorophenyl H phenyl Phenyl 33 4-chlorophenyl H H1,3-thiazol-2-yl

EXAMPLES 34-59

The following compounds were synthesized according to the methodsdescribed above:

Compound R¹ R² R³ 34 phenyl H phenyl 35 3-thienyl H phenyl 36 2-pyridylH phenyl 37 4-chlorophenyl H Phenyl 38 5-chloro-2-thienyl H phenyl 392-thienyl H phenyl 40 1,3-thiazol-2-yl H phenyl 41 phenyl H4-fluorophenyl 42 phenyl H 2-naphthyl 43 2-chlorophenyl H 2-thienyl 442-pyridyl H 2-thienyl 45 methyl H 2-thienyl 46 2-pyridyl H 2-pyridyl 47phenyl H 2-pyridyl 48 methyl H 2-pyridyl 49 5-chloro-2-thienyl H3-thienyl 50 phenyl H 3-thienyl 51 3-thienyl H 3-thienyl 52 phenyl H5-chloro-2-thienyl 53 3-thienyl H 3-thienyl 54 phenyl H 2-furyl 55phenyl phenyl H 56 phenyl phenyl phenyl 57 4-chlorophenyl H1,3-thiazol-2-yl 58 methyl H 1,3-thiazol-2-yl 59 phenyl H1,3-thiazol-2-yl

EXAMPLES 60-65

The following compounds were synthesized according to the methodsdescribed above:

Com- pound R¹ R² R³ R⁴ R⁵ R⁶ 60 4-fluorophenyl H H phenyl2-hydroxyphenyl H 61 4-chlorophenyl H H phenyl 5-bromo-2-hydroxy- H3-methoxyphenyl 62 4-chlorophenyl H H phenyl 2-hydroxyphenyl H 634-fluorophenyl H H Phenyl 3,5-dichloro-2- H hydroxyphenyl 644-fluorophenyl H H Phenyl 5-bromo-2-hydroxy- H 3-methoxyphenyl 654-chlorophenyl H H 1,3- 3,5-dibromo-2- H thiazol- hydroxyphenyl 2-yl

EXAMPLES 66-75

The following compounds were synthesized according to the methodsdescribed above:

Compound R¹ R² R³ R⁴ R⁵ 66 4-chlorophenyl H H phenyl 4-chlorobenzyl 674-fluorophenyl H H phenyl [5-(dimethylamino)-1- naphthyl]sulfonyl 684-chlorophenyl H H phenyl 4-[5-(dimethylamino)- 1-naphthyl]sulfonyl 694-chlorophenyl H H phenyl 1,3-benzodioxole-5- carbonyl 70 4-chlorophenylH H phenyl 2-naphthalenecarbonyl 71 4-chlorophenyl H H phenyl 4-bromo-1-benzenecarbonyl 72 4-fluorophenyl H H phenyl 4-cyano-1- benzenecarbonyl73 4-fluorophenyl H H phenyl (1-methyl-1H-2- imidazolyl)methyl 744-chlorophenyl H H phenyl 4-bromo-1- benzenesulfonyl 75 4-fluorophenyl HH phenyl 4-bromo- 1- benzenesulfonyl

EXAMPLES 76-99

The following compounds were synthesized according to the methodsdescribed above:

EXAMPLE 100 In Vitro Cytotoxicity Study

Human cancer cells gastric NUGC-3, colorectal SW480, lung A549, breastMCF7, uterus MES-SA, and its adriamycin-resistant MES-SA/D×5 sublinewere used in in vitro cytotoxicity assays. The human cells were seededat a cell density of 3000 or 4500 cells/100 μl/well in 96-wellflat-bottom plates and incubated for 24 hours at 37° C. in a 5% CO₂incubator. The compounds to be tested were dissolved in dimethylsulfoxide (DMSO) and further diluted into the culture medium forinhibiting (killing) these human cancer cells in vitro to have a finalDMSO concentration of 0.3%. Nine compounds of this invention, i.e.,Compounds 6, 73, 74, 72, 71, 69, 68, 70, and 75, were prepared inculture media for testing at a range of concentrations from 10, 1, 0.1,0.01 to 0.001 μM. Each compound solution (200 μl/well) was duplicated intwo wells of the cell plates and was treated for 72 hours at 37° C., 5%CO₂ in an incubator. 0.3% DMSO was used as the vehicle control. Acalorimetric assay using3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS) and phenazine methosulfate (PMS) was used to determine the potencyof the tested compounds. This assay measured cell viability based on thecellular activity in conversion of a tetrazolium salt into a coloredsoluble formazan product. The optical density (OD) values were measuredat 490 nm with a 1420 multilabel counter VICTOR® from Wallac (Turku,Finland). All of the measured values were subtracted with that of theblank control wells without cells before further calculations. Theefficacy data are expressed as a percentage normalized to the vehiclecontrols as calculated in the following formulae. Inhibitory potency (%of vehicle control)=[(OD490_(compound)−OD49O_(blank))/(OD490_(vehicle)−OD490_(blank))]×100%. The concentration of atest compound that inhibits 50% of the cellular activity (IC₅₀) wasdetermined.

All the tested compounds unexpectedly exhibited a broad spectrum ofanticancer activities among all the six used human cancer cell lines.

EXAMPLE 101 Evaluation of In Vivo Anticancer Activity

The in vivo anticancer activities of the compounds were evaluated by thefollowing murine leukemic P388 model. Inbred female DBA/2J mice of 4-5week-old were purchased from the National Laboratory Animals Breedingand Research Center, Taipei, Taiwan, ROC. Murine leukemic P388 cellswere purchased from the Japanese Collection of Research Bioresources,Japan. P388 cells were cultured and propagated in RPMI1640 mediumsupplemented with 50 μM 2-mercaptoethanol and 10% fetal bovine serum.Mice at the age of 6 weeks were grouped as the treatment, negativecontrol and positive control groups at 7 to 8 mice per group. All micewere intravenously inoculated with the P388 cells at one million permouse one day before the treatments initiated. Compound 6 was dissolvedin dimethyl sulfoxide (DMSO) and then diluted in 0.5% carboxymethylcellulose or a Cremophor-based vehicle with the final concentration ofDMSO less than 0.5%. Different treatment groups were orally (P.O.) orintravenously (I.V.) given, respectively, with Compound 6 of differentdoses for a pharmacological dose-response relationship. The mice of thenegative control group were treated with the dosing vehicle only. Apositive control, doxorubicin 10 mg/kg given by an intravenousinjection, was included. The cancer cell-inoculated animals weremonitored twice daily. Survival fractions of the mice were recorded. Thetime on which 50% of the P388-inoculated mice were still surviving isdefined as the medium survival time and was used to calculate thepercentage (normalized to the medium survival time of the control group)of increased in life span after treatment, which was then served as theindex of treatment response.

The results showed that Compound 6 unexpectedly increased the survivalrate of the inoculated mice.

OTHER EMBODIMENTS

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1-22. (canceled)
 23. A compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is alkyl, phenyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, optionally substituted with alkoxy, halo, cyano, nitro, or haloalkyl; or hydrogen; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is hydrogen, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo or alkyl.
 24. The compound of claim 23, wherein X is NH₂; R₂ is hydrogen; and R₃ is phenyl, furyl, or thienyl.
 25. The compound of claim 24, wherein the compound is


26. A compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is alkyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, optionally substituted with alkoxy, halo, nitro, or haloalkyl; or hydrogen; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is phenyl optionally substituted with halo, alkoxy or alkyl.
 27. The compound of claim 26, wherein X is NH₂; R₂ is hydrogen; and R₃ is phenyl, furyl, or thienyl.
 28. The compound of claim 27, wherein the compound is


29. A compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is hydrogen or alkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is hydrogen, alkyl, phenyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, in which phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl is optionally substituted with alkoxy, halo, nitro, or haloalkyl; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is hydrogen, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo or alkyl.
 30. The compound of claim 29, wherein X is NH₂; R₂ is hydrogen; and R₃ is phenyl, furyl, or thienyl.
 31. The compound of claim 30, wherein the compound is

32-33. (canceled)
 34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is alkyl, phenyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, optionally substituted with alkoxy, halo, cyano, nitro, or haloalkyl; or hydrogen; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is hydrogen, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo or alkyl.
 35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is alkyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, optionally substituted with alkoxy, halo, nitro, or haloalkyl; or hydrogen; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is phenyl optionally substituted with halo, alkoxy or alkyl.
 36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is hydrogen or alkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is hydrogen, alkyl, phenyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, in which phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl is optionally substituted with alkoxy, halo, nitro, or haloalkyl; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is hydrogen, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo or alkyl. 37-38. (canceled)
 39. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is alkyl, phenyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, optionally substituted with alkoxy, halo, cyano, nitro, or haloalkyl; or hydrogen; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is hydrogen, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo or alkyl.
 40. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is halo or haloalkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is alkyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, optionally substituted with alkoxy, halo, nitro, or haloalkyl; or hydrogen; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is phenyl optionally substituted with halo, alkoxy or alkyl.
 41. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of the following formula:

wherein X is —NR_(a)R_(b) or —N═CR_(c)R_(d), in which each of R_(a) and R_(b), independently, is hydrogen or alkyl, arylalkyl, heteroarylalkyl, arylcarbonyl, heteroarylcarbonyl, arylaminocarbonyl, or arylsulfonyl, in which aryl or heteroaryl is optionally substituted with alkoxy, halo, nitro, cyano, haloalkyl, or phenyl optionally substituted with halo; and each of R_(c) and R_(d), independently, is hydrogen, halo, or phenyl optionally substituted with hydroxy, halo, alkyl, haloalkyl, alkoxy, or amino; phenylsulfonyl substituted with cyano, halo, oxo, or amino; phenylcarbonyl substituted with cyano, halo, oxo, or amino; naphthalenylsulfonyl substituted with cyano, halo, oxo, or amino; naphthylcarbonyl substituted with cyano, halo, oxo, or amino; or alkyl optionally substituted with halo, phenyl optionally substituted with alkyl, halo, or hydroxy, or imidazolyl optionally substituted with alkyl, halo, or hydroxy; R₁ is hydrogen, alkyl, phenyl, haloalkylphenyl, phenylalkyl, diphenylalkyl, pyridinylalkyl, phenyloxadiazolylalkyl, phenylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, phenylaminocarbonyl, or phenylsulfonyl, in which phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl is optionally substituted with alkoxy, halo, nitro, or haloalkyl; R₂ is hydrogen, alkyl, phenyl, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo; and R₃ is hydrogen, furyl, thienyl, pyridinyl, oxadiazolyl, or isoxazolyl, optionally substituted with halo or alkyl.
 42. The method of claim 39, wherein X is NH₂; R₂ is hydrogen; and R₃ is phenyl, furyl, or thienyl.
 43. The method of claim 40, wherein X is NH₂; R₂ is hydrogen; and R₃ is phenyl, furyl, or thienyl.
 44. The method of claim 41, wherein X is NH₂; R₂ is hydrogen; and R₃ is phenyl, furyl, or thienyl. 